Bipolar Disorder
History
• “Manic depressive insanity” used by Kraepelin (1921)
• Manic depression rare in children
• “The universal experience is striking, that the attacks of manicdepressive insanity…never lead to profound dementia, not even
when they continue throughout life almost without
interruption…As a rule, the disease runs its course in isolated
attacks more or less sharply defined from each other or from
health, which are either like or unlike, or even very frequently are
the perfect antithesis.”
• Was misdiagnosed as schizophrenia (1978)
• Retrospective reports show that 3-5% of adults had onset of
symptoms before age 10
DSM-V Criteria
• Seen as a bridge between schizophrenia disorders and depressive
disorders
• Many disorders fall under the Bipolar umbrella
• Criterion A: 1+ manic episode(s), symptoms nearly all day every day
for a week or a hospitalization
• Elevated or irritable mood, more energetic, possible psychotic
symptoms
• Criterion B: Must have 3 of 7 symptoms during change in mood:
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Inflated self-esteem/grandiosity
Decreased need for sleep (different from insomnia)
More talkative than usual, pressure to keep talking
Thoughts racing, flight of ideas
Increase in goal-directed activity or psychomotor agitation
Risk-taking behavior (spending sprees, sexual behavior)
• Depressive mood possible but not required.
DSM-V Criteria
• Bipolar II involves episodes of hypomania and depression
• Hypomania requires the same symptoms as mania – just
shorter duration (4-6 days rather than 7+ days).
• Criterion B stays the same
• Child experiencing (hypo)manic episode
DSM Schematic
Environmental
Factors
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Genetics
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Circadian rhythm
disruption
Stress
Exact genetics
unknown
Neurobiological
Substrate
Psychotherapy
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Medication
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Catecholamine
deficiency/dysfunction
Amygdala dysfunction
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Lithium
Other mood
stabilizers
Antipsychotics
Secondary Features
Core Features
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Mania
Depressed, irritable mood
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Risk taking
Inattention
Poor academic
performance
Social difficultues
Suicidal ideation
Onset and Course
• Onset often follows stressful events, often depressive mood
first
• Sleep loss may mediate link
• Average age of onset is 18
• Remission gets shorter as time goes on, especially if left
untreated
• Those with a diagnosis of bipolar disorder have a 15x higher
risk of suicide attempts than the general population
• Some studies (COBY) report 35% higher
• Functionality between episodes can vary greatly Bipolar
disorder associated with delayed motor milestones, speech
problems and delays, reduced psychomotor functioning, and
low educational achievement, (Sigurdsson et al 1999, van Os
et al 1997)
Onset and Course
• Kids with a Diagnosis of BD I or II will likely persist with a BD
diagnosis in adulthood
• Depends on phenotype
• Lower performance on cognitive tests
• Could lead to impairment in work function commonly seen,
which would lead to lower SES also observed in adult populations
of BD
• Could be due to attentional difficulties
Differences in Children
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More chronic course
Episodes have shorter duration (hours)
Kids spend more time symptomatic overall
Irritability – question of whether it is a necessary condition
Kids may take on many new projects, have inappropriate
sexual thoughts
• Not due to abuse
• Higher rates of comorbidity
• May be because symptoms overlap too much in the DSM
• Higher levels of emotional and behavioral dysregulation
Comorbidity
Disorder
% of BD children with disorder
ADHD
11-75%
Oppositional Defiant Disorder
46.4-75%
Conduct Disorder
5.6-37%
Anxiety Disorders
12.5-56%
Substance Abuse Disorders
0-40%
Diagnostic Difficulties
• Diagnostic difficulties in children
• Euphoria particularly difficult
• Look for behavior that is recurrent, inappropriate in context, above and
beyond the child’s normal behavior – i.e. change from his or her baseline
• Can be difficult to see in a clinical setting.
• May experience irritability instead
• Grandiose beliefs usually take the form of best in the class, smartest
in the school, best at their sport, etc. Kids can exaggerate like this
anyway.
• Younger kids can’t distinguish between fantasy and reality
• Poor social skills
• Symptom counting is not enough – a global picture is necessary for a
diagnosis
• Low concordance rate of parent/child ratings for mania
• Episodes are key to diagnosis
• Diagnosis can greatly depend on what assessments are used
Prevalence
• Estimated to be 0.6% of the population with no real
differences between males and females (DSM)
• Men may have an earlier onset
• Males and females may differ in symptom presentation
• The number of adolescents (0-19) diagnosed with BD
increased 40x in 9 years (25 diagnosed to 1003 diagnosed),
(Moreno, Laje, Blanco, Jiang, Schmidt, & Olfson 2007)
• Is this due to a true increase, more recognition, or misdiagnoses?
• Strong genetic component
Etiology
• Strong genetic link
• Heritability rates hover around 67-72% based on twin studies
• Family history is one of the strongest and most consistent risk
factors
• Adult relatives of those with BD (1st-degree) have a 10x
increase of diagnosis
• Likely shares a genetic origin with mood disorders – some
combination of genetics predisposes one to an affective
disorder
Genetics/Family Influences
• Romero (2005) compared healthy families (27) to families
where at least one parent had Bipolar Disorder (23)
• 3.7% of HF had a child with a mood disorder
• 71% of BPD families had a child with a mood disorder
• 38% BPD I or II
• 13% depression
• Also saw cyclothymic disorder, dysthymic disorder
• Used the Family Environment Scale (FES)
• Compared to normative FES data, BPD families had higher
independence and conflict, lower cohesion and expressiveness
Social/Environmental Contributions
• Hard to determine
• Slightly more common in high-income countries (DMS reports
1.4% prevalence vs 0.7%)
• Childhood abuse may affect development of disorder
• Garner, Goldberg, Ramirez, & Ritzler (2005) studied childhood
abuse in children with BD
• N = 100 (BD I – 73, BD II = 27)
• Appx half identified either childhood physical, sexual, or
emotional abuse, and/or physical or emotional neglect
• Median age of first (hypo)manic episode = 17.5
• Kids with severe abuse had significantly lower age on onset,
higher severity of current level of manic symptoms, higher risk of
substance use, more rapid cycling
• Increasing number of abuse forms positively associated with
number of suicide attempts
Social/Environmental Contributions
• Childhood depression with psychotic features may predispose
children to later development of mania
• Goldberg, Harrow, & Whiteside study
• 15-year study of 74 patients hospitalized for unipolar depression
• 41% of cohort experienced mania or hypomania
• 15% had manic episode
• Patients with family history of BD showed higher rates of conversion
to BD themselves
• Findings were nonsignificant
• Psychotic features during depression seem to be an additional risk
factor
Neurobiological Substrate
• No single underlying hypothesis for pathophysiology (“No smoking gun, but a
biological crime scene.”)
• Decreased cerebral blood flow and metabolism as compared to controls and
patients with unipolar depression
• State dependent
• Decrease in DLPFC metabolism and blood flow
• Executive functions such as working memory, planning, abstract reasoning
• Enlarged ventricles – connected to mania?
• Smaller amygdala
• Possible deficiency in one or more monoamines
• Treatment that increases these can precipitate mania
• In a postmortem study, no differences in norepinepherine, serotonin, or
dopamine were found
• Decrease in BDNF
• Increased white matter hyperintensities
• Seen in normal aging and linked to mild cognitive decline
• Seen in patients with BD and MDD
• Similar HPA-axis disregulation as found in unipolar depression
Neuropsychological Deficits
• Comobidities make it challenging to assess.
• Impaired perception of facial expression seen in both child
and adult populations (narrow phenotype, while euthymic).
• Children seem to have more difficulties with adult faces as
opposed to child faces (McClure 2005).
• Impairments in working memory and processing speed
• Impaired verbal learning
• Particularly in kids with comorbid ADHD
• No differences in brain anatomy of BD kids with comorbid
ADHD as compared to those without (DelBello 2004)
• Lithium probably impairs psychomotor speed, verbal memory
Neuropsychological Deficits
• Dickstein (2004) studied children with BD and gender- and
age-matched controls (n = 42, ages 10-15, 13 euthymic, 8
hypomanic)
• Found impaired attentional set-shifting and visuospatial
memory
Phenotypic Differences
• Liebenluft et al proposed four subtypes for bipolar disorder
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Narrow – meet DSM criteria
Hypomania NOS – Short episodes, hallmark symptoms
Irritable hypomania – irritability instead of euphoria, episodic
Broad – chronic hyperarousal/irritability
• This phenotype is the most controversial
• Also called Severe Mood Dysregulation
• Probably means different etiologies, genetic contributions,
course, treatment response, outcome
The Irritability Question
• Wozniak, Biederman, et al (1995) study found mania present in 16%
(43) of referred children (n = 262)
• Used K-SADS
• These kids exhibited impaired psychosocial functioning
• High comorbidity (depression, psychosis, ADHD, anxiety disorders,
CD, ODD)
• Children were predominantly irritable/mixed mood
• 84% mixed mood
• 77% extreme, persistent irritable mood
• 5% manic
• Of 43 manic children, 42 also diagnosed with ADHD
• 70% of manic children had onset before age 5
• Course
• 84% chronic
• 16% episodic
• 23% had symptoms that were always present
Bipolar NOS
• Brotman et al drew data from the Great Smoky Mountains
Study
• N = 1420, 96 had the broad phenotype, or SMD
• None experienced a classic (hypo)manic episode
• 2% of their parents were diagnosed with BD
• Development of MDD was the only statistically significant
association (odds ratio 7.2, CI 1.3-38.8)
• Youths with BD I or II diagnoses tend to keep the diagnosis
throughout their lives (Birmaher et al 2006)
• i.e. Clinical course differs
Bipolar NOS
• COBY study - 4-year longitudinal study of bipolar youth
• Question over whether euphoria could/would be observed in
children, or if child BD only includes irritability
• Studied youth with Bipolar Disorders I, II, and NOS
• NOS kids were irritable but had episodic irritability, which
distinguishes them from constantly irritable BD-NOS group
• Episodic irritability lasted for about 2 days, which doesn’t qualify for
hypomania
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1/5 of BP-II converted to BP-I
1/4 of BP-NOS converted to BP-I or II
Euphoria in 92% of children, irritability in 84%
Age of onset, duration of mood symptoms, low SES, and psychosis all
predicted outcome
• Compared youth to adults, youth spent more time symptomatic and
had more episodes and mood symptom changes
Bipolar NOS
• Stringaris et al. followed children with BD narrowly defined
(93) and SMD (84) at 6-month intervals for average of 2 years
• 50 BD children had a manic or mixed episode during follow-up
• 1 SMD child had manic or mixed episode
• SMD kids did develop MDD
• Suggests they are from different populations
Treatment - Medication
• Early studies found lithium to be effective in teens (Annell
1969)
• Lithium flows into neurons during depolarization
• Can conceptualize as decreasing sensitivity to fire
• May increase cell growth in the hippocampus (like SSRI’s)
• Animal study supports this – Yoneyama et al 2014
• Lethal doses can be as small as twice theraputic dose
• Anticonvulsants, atypical (2nd generation) antipsychotics
sometimes used
Treatment - Psychotherapy
• In adjunct to medications, not a substitute for
• Interpersonal and social rhythm therapy (IPSRT)
• Developed specifically for BD
• Individuals vulnerable to disrupted circadian rhythms, abnormal
sleep-wake cycles, stressful events, medication nonadherence
• Sleep deprivation can precipitate mania
• Therapy targets these issues
• Some empirical evidence, not greatly studied
Treatment - Psychotherapy
• Frank et al studied IPSRT and Clinical Management (CM) in 82
patients with BD
• All patients were on medication
• Treatment was done in two phases – acute and preventative
• Some patients kept the same therapy, some switched
• Four groups:
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Acute IPSRT and preventative IPSRT
Acute IPSRT and preventative CM
Acute CM and preventative IPSRT
Acute CM and preventative CM
• 34% experienced recurrence over 1 year
• Outcomes did not depend on type of treatment
• Switching treatment was significantly associated with relapse
Treatment - Psychotherapy
• Child Family Focused CBT
• Family dynamics act as a moderator between treatment response
and relapse rates
• 12 sessions, 1 hour each, child and parents
• Talk about communication skills, sticking to a routine, medication
adherence
• Pavulurti (2004) study of 34 families showed reduction in
problems as compared to pre-treatment
New Schematic
Environment
Genetics
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Abnormalities
providing
common link
between mood
disorders
Neurobiological
Substrate
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Other
Genetics
Medications
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SMD
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Chronic irritability
and arousal
Severe reactions to
stimuli, rages
Outcome
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MDD
Dysthymia
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Monomine deficiency
HPA dysfunction
Decreased cerebral
blood flow and
metabolism
Enlarged ventricles
White matter
hyperintensities
Smaller amygdala
Decrease in BDNF
Psychotherapy
Bipolar Disorder
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Secondary
Features
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Inattention
Poor academics
Peer difficulties
Suicidal ideation
Family conflict
Restlessness
Increased
psychomotor
agitation
Sleep loss
Stress
Interpersonal conflict
Abuse
Changes in routine
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Narrow
• Episodes of mania
Hypomania NOS
• Shorter episodes
• Hallmark symptoms
Irritable hypomania
• Episodic irritability
Outcome
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BD I and II
Anxiety Disorders
Substance abuse
Challenges
• Differential diagnosis
• Criterion B symptoms include decreased need for sleep, high
distractability, and more energy
• This can look a lot like other disorders
• BD and schizophrenia can look similar, particularly if there is
psychosis in BD
• No consensus on standardized screening instrument. For
example, Biederman frequently uses the Child Behavior
Checklist. He finds high scores on attention problems,
aggression, and depression/anxiety.
• Youngstrom prefers the Parent General Behavior Inventory
and Child Mania Rating Scale
Challenges
• Few longitudinal studies
• Those that do exist are childhood to adolescence or adolescence
to adulthood, generally not both
• Many studies combine children and adolescents
• Not many studies compare children to adults
• Disorder may be better viewed dimensionally rather than
dichotomously
• When diagnosing, be careful to ask the right person the right
questions. For example, parents won’t know as much about
homicidal thoughts as the children in question
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